Du forlater nå GSKs nettsider

Denne lenken tar deg til en nettside som ikke tilhører GSK. GSK er ikke ansvarlig for, går ikke god for og aksepterer intet ansvar for informasjon eller meninger på nettsteder til tredjeparter

Fortsett

Tilbake

Nucala Phase II and III clinical study summaries

Nucala has been investigated in three key clinical trials in severe refractory eosinophilic asthma: DREAM, MENSA and SIRIUS. Find out more about the design and results of these studies.

DREAM 3 – A dose-ranging study to evaluate the efficacy and safety of mepolizumab

The DREAM (Dose Ranging Efficacy And safety with Mepolizumab) study was a randomised, multicentre, double-blind, placebo-controlled, phase IIb clinical trial that investigated the efficacy and safety of mepolizumab in patients with severe refractory eosinophilic asthma. 1

Study design

The study included 616 patients, aged 12–74 years, with a history of severe asthma exacerbations (two or more, requiring systemic corticosteroid treatment in the previous 12 months) and evidence of eosinophilic inflammation as shown by one or more of the following criteria: 1

  • sputum eosinophil count of 3% or more
  • exhaled nitric oxide concentration of 50 ppb or more
  • asthma-related peripheral blood eosinophil count of ≥300 cells/μL (≥0.3 x 109 cells/L)
  • prompt deterioration of asthma control after a ≤25% reduction in regular maintenance inhaled or oral corticosteroids

Patients were randomised in a 1:1:1:1 ratio to receive one of three doses of intravenous (IV) mepolizumab (75mg, 250mg or 750mg)* or placebo,† every 4 weeks 1

*unlicensed doses/route of administration
†when both were added to high dose ICS and an additional maintenance treatment(s)

Key efficacy findings

Treatment with mepolizumab provided:

  • Significant reductions in the rate of clinically significant exacerbations (primary endpoint) (defined as episodes of acute asthma requiring treatment with oral corticosteroids [OCS], admission/visit to an emergency department [ED]) vs. placebo (Nucala 75mg: 1.24 vs. placebo: 2.4, 48% reduction, 95% CI 31-61%; p<0.0001; Nucala 250mg: 1.46 vs. placebo: 2.4, 39% reduction, 95% CI 19-54%; p=0.0005; Nucala 750mg: 1.15 vs. placebo: 2.4, 52% reduction, 95% CI 36-64%; p<0.0001) 1
  • Reductions in the rate of exacerbations requiring hospitalisation or ED admissions/visits vs. placebo (secondary endpoint) (Nucala 75mg: 0.17 vs. placebo: 0.43, 60% reduction, p<0.05; Nucala 250mg: 0.25 vs. placebo: 0.43, 42% reduction,ns; Nucala 750mg: 0.22 vs. placebo: 0.43, 48% reduction ns) 1

Cumulative number of exacerbations over 52 weeks 1

Adapted from Pavord et al. 2012.

Nucala is indicated as an add-on treatment for adult patients with severe refractory eosinophilic asthma. 2

Nucala is only licensed for subcutaneous use (SC) and only at a dose of 100mg. 2

Key safety findings

  • Incidence of serious adverse events (AEs) was similar across treatment groups 1
  • The most frequently reported AEs were headache and nasopharyngitis 1
  • The most frequent drug-related AE was injection site reaction 1

Summary

  • All doses of mepolizumab significantly reduced clinically significant exacerbations vs. placebo (p<0.05) and were well tolerated, when both were added to high dose ICS and an additional maintenance treatment(s)

MENSA3 - Investigating the safety and efficacy of Nucala add-on therapy in patients with severe refractory eosinophilic asthma

The MENSA (Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma) study was a randomised, multicentre, double-blind, double-dummy, placebo-controlled, phase IIIa clinical trial that investigated the safety and efficacy of mepolizumab in patients with severe refractory eosinophilic asthma. 3

Study design

The study included 576 patients,aged 12–82 years* entry criteria, which were informed from the DREAM study outcomes, included: 3

  • Dependency on high dose ICS and an additional maintenance treatment(s) for at least 3 months, with or without OCS
  • ≥2 asthma exacerbations in the prior 12 months
  • Blood eosinophil levels of ≥150 cells/μL (≥0.15 x 109 cells/L) at initiation of treatment or ≥300 cells/μL (≥0.3 x 109 cells/L) in the prior 12 months

Patients were randomised to receive Nucala 100mg subcutaneous (SC), mepolizumab 75mg IV† or placebo in a 1:1:1 ratio added on to high dose ICS and an additional maintenance treatment(s). 3Only the data from the Nucala 100mg SC vs. placebo comparison are reported here.

*Nucala is indicated for SC use in adult patients with severe refractory eosinophilic asthma only.
†Unlicensed dose/route of administration

Adapted from Ortega et al. N Engl J Med 2014. 3

*Patients who received mepolizumab 75mg IV also received placebo SC, patients who received Nucala 100mg SC also received placebo IV and patients in the placebo arm received placebo both IV and SC.

Key efficacy findings

Reduction in exacerbation frequency vs. placebo at Week 32 (primary endpoint)

Nucala added to high dose ICS and an additional maintenance treatment(s) provided the following benefits compared with placebo added on to high dose ICS and an additional maintenance treatment(s):

  • Significant reduction in clinically significant exacerbations* by 53% (primary endpoint, 95% CI 36-65%; p<0.001) 3
  • Significant reduction in exacerbations resulting in hospitalisations and/or ED visits by 61% (secondary endpoint, Nucala: 0.08/year, placebo: 0.2/year; 95% CI 17-82%; p=0.02)† 2
  • Significant reduction in exacerbations resulting in hospitalisations by 69% (secondary endpoint: Nucala: 0.03/year, placebo: 0.10/year; 95% CI 9-89%; p=0.03) † 2
  • Clinically meaningful improvement in health-related quality of life (SGRQ total score) by 7.0 units (secondary endpoint, 95% CI -10.2 to -3.8; p<0.001). 3
    • SGRQ is a validated disease-specific health status assessment for use in asthma and COPD and a difference of ≥4.0 units is considered clinically meaningful 45
  • Improvement in lung function (as measured by pre-bronchodilator FEV1) by 98mL (secondary endpoint, 95% CI 11-184mL; p=0.03). 2

*Defined as worsening of asthma that required use of systemic corticosteroids or hospitalisation and/or emergency department visit 1

†Statistical significance for these secondary endpoints cannot be inferred due to the hierarchical ‘gatekeeping’ approach used. The p-values provided are unadjusted for multiple comparisons.

Key safety findings

In placebo-controlled clinical trials with Nucala (added to high dose ICS and additional maintenance treatment[s]), the rate of adverse events was similar across treatment arms, with the exception of injection site reactions (9% (17/194) for Nucala, 3% (6/191) for placebo). 2

  • Incidence of AEs was 78% (152/194) in the Nucala group and 83% (158/191) in the placebo group 3
  • Incidence of serious AEs was 8% (16/194) in the Nucala group and 14% (27/191) in the placebo group 3
  • The most frequently reported AEs were nasopharyngitis and headache 3

Summary

  • The MENSA study demonstrated the benefits of Nucala in terms of exacerbation reduction in patients with severe refractory eosinophilic asthma. Improvements in quality of life and lung function were also observed but statistical significance cannot be inferred due to the hierarchical ‘gatekeeping’ approach used. The p-values provided are unadjusted for multiple comparisons 3
  • Furthermore, the the rate of adverse events was similar across treatment arms, with the exception of injection site reactions (9% (17/194) for Nucala, 3% (6/191) for placebo) 3

SIRIUS 6- Investigating the corticosteroid-sparing effect of Nucala as an add-on therapy in patients with severe refractory eosinophilic asthma

The SIRIUS (SteroId ReductIon with MepolizUmab Study) trial was a randomised, multicentre, double-blind, placebo-controlled, parallel-group, phase IIIa clinical trial that investigated the effect of Nucala in reducing the use of maintenance OCS while maintaining asthma control in patients with severe refractory eosinophilic asthma. 6

Study design

The study included 135 patients, aged 16-74 years and entry criteria included: 6

  • Dependency on high dose ICS and an additional maintenance treatment(s),
  • Maintenance treatment with OCS for at least 6 months (5-35mg/day prednisone or equivalent)
  • Blood eosinophil level of ≥150 cells/μL(≥0.15 x 109 cells/L) at the start of the study or ≥300 cells/μL(≥0.3 x 109 cells/L) in the prior 12 months

Unlike the DREAM and MENSA trials, patients were not required to have a history of exacerbations but all patients were maintained on daily OCS medication for at least 6 months prior to the study. 6

Patients were randomised to receive Nucala 100mg SC or placebo in a 1:1 ratio added on to OCS, high dose ICS and an additional maintenance treatment(s). 6

Adapted from Bel et al. N Engl J Med 2014. 6

*During the optimisation phase (3–8 weeks before study start), OCS dose was reduced weekly until there was an exacerbation in asthma symptoms or an increase of at least 0.5 points from the visit 1 score on the asthma control questionnaire (ACQ)-5. The median OCS dose following optimisation was 10.0mg for patients receiving Nucala and 12.5mg for placebo recipients. 6

†During the reduction phase (Weeks 4–20), OCS dose was reduced according to a pre-specified schedule by 1.25mg to 10mg per day every 4 weeks on the basis of asthma control and symptoms of adrenal insufficiency. 6

Key efficacy findings

The odds of achieving a reduction in OCS dose while maintaining symptom control were 2.39 times higher in patients receiving Nucala compared with placebo recipients, when both were added to high dose ICS and an additional maintenance treatment(s) (primary endpoint, 95% CI 1.25-4.56; p=0.008). Median OCS dose at baseline (during optimisation phase) was 10mg for Nucala (n=69) and 12.5mg for placebo (n=66). 6

  • 54% (37/69) of Nucala patients achieved at least a 50% reduction in the daily OCS dose compared with 33% (22/66) of patients receiving placebo, when both were added to high dose ICS and an additional maintenance treatment(s) (secondary endpoint, odds ratio 2.26 (95% CI 1.10-4.65); p=0.03) 6
  • 54% (37/69) of Nucala patients achieved a reduction in the daily OCS dose to ≤5mg compared with 32% (21/66) of subjects receiving placebo, when both were added to high dose ICS and an additional maintenance treatment(s) (secondary endpoint, odds ratio 2.45 (95% CI 1.12-5.37); p=0.02) 6
  • The median percentage reduction in daily OCS dose was 50% (95% CI 20.0 to 75.0%) in the Nucala group, compared with 0% in the placebo group (secondary endpoint, p=0.007) 6
  • 14% (10/69) of Nucala patients achieved a total (100%) reduction in OCS compared to 8% (5/66) of subjects receiving placebo when both were added to high dose ICS and an additional maintenance treatment(s) (odds ratio 1.67 (95% CI 0.49-5.75) p=ns) 7

Key safety findings

The safety profile was similar between treatment groups: 6

  • Incidence of AEs was 83% (57/69) in the Nucala group and 92% (61/66) in the placebo group
  • Incidence of serious AEs was 1% (1/69) in the Nucala group and 18% (12/66) in the placebo group
  • The most frequently reported AEs were headache and nasopharyngitis
  • No serious AEs related to immunogenicity were reported

Summary

The SIRIUS study showed that, in patients requiring daily OCS therapy to maintain asthma control, Nucala had a significant OCS-sparing effect and had a safety profile similar to placebo.

References:

  1. Pavord P, Korn S, Howarth P et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 2012; 380(9842):651-59.
  2.  Nucala SmPC.
  3. Ortega HG, Liu MC, Pavord ID et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med 2014; 371(13):1198-1207.
  4. Jones PW. Interpreting thresholds for a clinically significant change in health status in asthma and COPD. Eur Resp J 2002; 19(3):398-404.
  5. Jones PW, Quirk FH, Baveystock CM et al. A self-complete measure of health status for chronic airflow limitation. The St. George's Respiratory Questionnaire. Am Rev Respir Dis 1992; 145(6):1321-1327.
  6. Bel EH, Wenzel SE, Thompson PJ et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med 2014; 371(13):1189-1197.

Nucala is a trademark of the GSK group of companies